The prompt recognition, evaluation, and management of an acute decompensation in any hospitalized patient directly impacts the clinical outcomes. In this chapter, common presentations, evaluation, and initial management of hospitalized neurologic patients who develop sepsis, severe sepsis, and septic shock are reviewed. Sepsis-associated complications of encephalopathy, ICU-acquired weakness, and acute kidney injury are discussed. A practical approach to these patients is presented to help the reader establish an efficient diagnostic evaluation and management strategy.

What is the differential diagnosis for the patient’s presentation?

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  Any patient presenting with fever, hypotension, and tachycardia should be assumed to be septic until proven otherwise.

  
  
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  Autonomic dysreflexia typically presents with hypertension, but should be considered due to the presence of an upper thoracic cord lesion.¹

  
  
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  Serotonin syndrome and neuroleptic malignant syndrome are potential causes of acute-onset fever, tachycardia, and encephalopathy in the proper clinical setting, but are also more likely to result in hypertension. It is necessary to review recently administered medications when evaluating patients with acute-onset encephalopathy with or without accompanying changes in vital signs.

  
  
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  Both transfusion-associated sepsis due to infusion of a product containing a microorganism and anaphylactic transfusion reactions can produce this constellation of symptoms abruptly.

  
  
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  While the patient’s initial presentation included “shaking,” generalized shaking is not consistent with an epileptic event when consciousness is preserved except in rare frontal seizure disorders. In this patient, the “shaking” that was described represented rigors and should alert the team to evaluate for infection.

In the above-mentioned vignette, the temporal onset during plasma exchange suggests either transfusion-associated severe sepsis or an anaphylactic transfusion reaction.

What are sepsis, severe sepsis, and septic shock?²

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  Systemic inflammatory response syndrome (SIRS) criteria can help identify patients who should be further evaluated for infection, but this syndrome is nonspecific and may result from a variety of acute systemic or neurologic illnesses.

  
  
  
  
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    Patients meeting >1 of the 4 listed abnormalities meet diagnostic criteria for SIRS:

    
    
    
    
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      Temperature <36°C or >38°C

      
      
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      Heart rate >90 beats per minute (bpm)

      
      
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      Respiratory rate >20 breaths per minute or PaCO₂ <32 mmHg

      
      
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      White blood cell count <4000 or >12,000/mm³ or >10% bands

    
    

  
  
  
  
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  Sepsis: Presence of SIRS criteria in addition to an infectious source

  
  
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  Severe sepsis: Sepsis with evidence of end-organ dysfunction, hypoperfusion (manifested by elevated lactate, encephalopathy, or decreased urinary output), or hypotension

  
  
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  Septic shock: Severe sepsis with hypotension unresponsive to fluid resuscitation with evidence of end-organ dysfunction

What are the potential sources of infection in this patient?

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  Transfusion of a microorganism during plasma exchange (rare)

  
  
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  Patients who are hospitalized for a prolonged period and who have reduced mobility are at increased risk for infection from multiple sources:

  
  
  
  
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    Indwelling urinary catheters

    
    
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    Central venous catheters

    
    
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    Ventilator- or hospital-acquired pneumonia

    
    
    
    
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      In patients with neurologic disease manifesting as weakness, aspiration must be included in the differential diagnosis and respiratory function monitored closely

    
    
    
    
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    Nasogastric tubes (sinusitis with prolonged use)

    
    
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    Decubitus ulcers

    
    
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    Surgical wounds

    
    
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    Antibiotic-associated diarrheal infection (typically due to Clostridium difficile)

  
  

What should the initial evaluation include?

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  Physical examination to evaluate for abnormal findings, which may suggest an infectious source or point toward a medication reaction (Table 48-1)

  
  
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  Laboratory evaluation for infection

  
  
  
  
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    Blood cultures (from a peripheral source and any central lines)

    
    
    
    
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      All cultures should be drawn before antibiotic administration, unless this would significantly delay therapy. Obtaining cultures before antibiotic administration increases the yield of the culture and helps to narrow antibiotic therapy once microbial susceptibilities are available. If cultures cannot be drawn within 45 minutes, antibiotic therapy should not be delayed and cultures drawn as soon as possible.³

    
    
    
    
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    Urinalysis with reflex urine culture

    
    
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    Sputum culture (if possible, culture the tracheal secretions as sputum cultures are not obtained from a sterile site)

    
    
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    Swab and culture any frank purulent material at surgical wound sites

    
    
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    Chest x-ray

    
    
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    Culture other indwelling drains (ie, ventriculostomy, lumbar drain, chest tube, etc) as clinically indicated

    
    
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    Consider lumbar puncture (LP)

  
  
  
  
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  Obtain baseline laboratory studies including complete blood count, chemistry panel, lactate, creatine kinase, arterial blood gas, and inflammatory markers (sedimentation rate, C-reactive protein)

  
  
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  C difficile PCR in stool in at-risk patients

  
  
  
  
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    Risk factors for severe C difficile infection include the following:⁴

    
    
    
    
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      Age >70 years

      
      
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      Leukocyte count >20,000 cells/mL

      
      
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      Albumin <2.5 g/dL

      
      
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      Creatinine >2 mg/dL

      
      
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      Small bowel obstruction/ileus

      
      
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      Evidence of colorectal inflammation on CT scan

    
    

  
  

How would the evaluation and management change if the patient was immunocompromised?

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  The initial evaluation does not differ for immunosuppressed patients. When the initial evaluation is unrevealing, consider less common infectious agents and consult an infectious disease specialist.

  
  
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  Because patients with depressed immunity may not present with a classic sepsis syndrome due to inability to mount a typical immune response, clinicians must maintain a high index of suspicion for infection in the setting of nonspecific symptoms such as altered mental status and tachycardia.

  
  
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  Immunocompromised patients are at risk for multiple opportunistic infections that can affect many different organ systems. Both infections that were acquired early in life and had previously been latent, and newly acquired infections can cause severe disease in these patients.⁵

What initial interventions are recommended in this patient?

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  The patient should receive early goal-directed therapy (within 3–6 h of symptom onset) with fluid resuscitation, empiric antibiotic coverage, and close vital sign monitoring.

  
  
  
  
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    Components of early goal-directed therapy (EGDT) are listed in Table 48-2.³

    
    
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    Initial fluid resuscitation with 30 mL/kg of a crystalloid solution if the patient is hypotensive or has a lactate >4 mmol/L.³

    
    
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    The mortality benefit of early goal-directed therapy persists when these measures are completed up to 18 hours after presentation.⁶

  
  
  
  
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  Initial antibiotic coverage is dependent on the suspected infectious source, but should include administration of broad-spectrum agents within 3 hours of patient presentation.⁷ The antibiotic regimen can be narrowed based on culture results in order to prevent the development of antibiotic resistance.

  
  
  
  
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    Administer antibiotics within the first hour in those patients presenting with septic shock, and within 3 hours in patients with severe sepsis without shock.³

    
    
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    The American Society of Clinical Oncology recommends that cancer patients with neutropenic fever be initiated on antibiotics within 1 hour of their presentation.⁸

  
  
  
  
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  The beneficial effect of EGDT was evaluated as compared to standard therapy in a recent randomized controlled trial. There was no difference in patient mortality between those that received standard care and those who underwent rigorous EGDT, following the established guidelines. This likely reflected the widespread adoption of the initial EGDT guidelines into normal clinical practice.⁹

  
  
  
  
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    A meta-analysis is planned when the Protocolized Management in Sepsis (ProMISe) trial is completed and may demonstrate benefits of EGDT in certain patient populations.

  
  

How do you monitor response to treatment?

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  Monitoring of patients with sepsis, severe sepsis, or septic shock is as outlined in the components of the early goal-directed therapy protocol,³ listed in Table 48-2.

  
  
  
  
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    Continuous monitoring of hemodynamics is essential to help guide continued management and specifically to ensure that EGDT goals are met and recognized when escalation of care is required.

  
  

What are the next steps?

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  The patient failed to adequately respond to the initial components of early goal-directed therapy. Vasopressor support and close monitoring in an intensive care unit (ICU) given his persistent hypotension and evidence of end-organ dysfunction (septic shock) are warranted.

  
  
  
  
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    The recommended first-line vasopressor agent is norepinephrine.³

    
    
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    In a prior study, the use of dopamine was associated with more adverse events, but did not affect overall mortality in a head-to-head comparison with norepinephrine.¹⁰

    
    
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    In patients in whom norepinephrine is not sufficient, epinephrine can be added to or substituted for norepinephrine. Alternatively, vasopressin could be added to norepinephrine, but is not recommended as initial monotherapy.³

    
    
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    In patients who demonstrate evidence of cardiac dysfunction despite a normal mean arterial pressure (MAP), ionotropic therapy with dobutamine can be used alone or in combination with vasopressors.³

    
    
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    Initiate vasopressor therapy within 6 hours of presentation when initial resuscitation measures are unsuccessful and the MAP remains below goal.³

  
  
  
  
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  The central venous access catheter must be removed in the presence of positive blood cultures from this site.

How can sepsis be prevented in patients with neurologic disease?

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  Frequent review of the patient’s medical problem list, vascular access and other invasive devices, and general condition can lead to earlier identification of potential sources for sepsis and earlier recognition and treatment of infections before sepsis develops. A checklist approach to daily rounds can lead to prompt removal of potential infectious sources when they are no longer required for the care of the patient. These checklists should incorporate bundles to standardize management of central lines, and is the current guideline for infection prevention in these patients.¹¹ This approach has previously been shown to decrease the rate of intravascular catheter-related infections.¹² Similar practices have been successfully implemented for the prevention of ventilator-associated pneumonia as well.¹³

  
  
  
  
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    Remove urinary catheters as soon as possible.

    
    
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    Remove central venous access catheters promptly when they are no longer necessary.

    
    
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    Wound care as needed for decubitus ulcers.

    
    
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    Hand hygiene by all caregivers.

    
    
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    Use of clean stethoscopes/medical equipment.

  
  

The differential diagnosis of delayed awakening in this patient includes:^14,15

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  Persistent effect of sedating or analgesic medications

  
  
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  Toxic/metabolic etiologies—sepsis-associated encephalopathy, electrolyte abnormalities (sodium, glucose, calcium), hyperammonemia, severe hypothyroidism, hypercapnia, hypoxia, renal or hepatic impairment

  
  
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  Effects of systemic inflammation/infection

  
  
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  Intracranial infection—cerebral abscess (particularly in the setting of focal neurologic findings), meningitis, encephalitis

  
  
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  Ischemic or hemorrhagic stroke—the latter being more likely if the patient is coagulopathic

  
  
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  Posterior reversible encephalopathy syndrome (PRES)

  
  
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  Nonconvulsive status epilepticus (Figure 48-1)

  
  
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  Toxidrome (ie, cefepime neurotoxicity or serotonin syndrome due to fentanyl use in the setting of long-acting serotonin reuptake inhibitors)

  
  
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  Neuroleptic malignant syndrome or parkinsonism-hyperpyrexia syndrome in the proper clinical context

  
  
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  CNS vasculitis

  
  
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  Malignant catatonia in a patient on psychoactive medications

The patient described above had the expected examination findings in sepsis-associated encephalopathy. His level of consciousness was depressed without focality, and myoclonic jerks were observed suggesting a metabolic derangement. It is not uncommon for patients hospitalized with acute illness, particularly when in an ICU, to develop disorientation, agitation, or deterioration in their level of consciousness. The differential diagnosis for encephalopathy in the ICU is broad, and thorough evaluation is required. We will focus primarily on encephalopathy associated with sepsis.

What are the presenting signs and symptoms of sepsis-associated encephalopathy?

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  Patients with sepsis-associated encephalopathy typically have nonspecific symptoms or signs, which may include:⁹

  
  
  
  
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    Impaired level of consciousness

    
    
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    Aberrant sleep-wake cycle

    
    
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    Hallucinations

    
    
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    Agitation

    
    
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    Changes in muscle tone

    
    
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    Abnormal involuntary movements

  
  

What does the clinical examination typically show in patients with sepsis-associated encephalopathy?

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  The examination is nonfocal. Patients will typically have impaired attention and a fluctuating level of consciousness. The patient may react to an apparent hallucination. While the ability to follow commands is variable, clearly focal findings are uncommon. In severely ill patients, delayed awakening from sedation or coma may be the initial presentation.

  
  
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  The presence of focal findings warrants consideration of alternative etiologies for the patient’s presentation.

What evaluation should be completed in patients with encephalopathy and sepsis?^14,15